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Genetic and pharmacological inhibition of dimethylarginine dimethylaminohydrolase 1 is protective in endotoxic shock.

AbstractOBJECTIVE:
The overproduction of vascular NO contributes toward the circulatory collapse observed in patients with septic shock. Dimethylarginine dimethylaminohydrolase (DDAH), which has 2 isoforms, metabolizes asymmetrically methylated arginines (asymmetric mono- or di-methylarginine), endogenously produced NO synthase inhibitors. We wished to investigate whether reducing DDAH1 activity, using genetic and pharmacological approaches, is protective during lipopolysaccharide-induced endotoxic shock.
METHODS AND RESULTS:
Experiments were conducted in DDAH1 heterozygous knockout mice (DDAH1(+/-)) or naive rats treated with a synthetic pharmacological DDAH inhibitor (L-257). We demonstrate for the first time that L-257 is DDAH1 selective using recombinant human DDAH proteins. DDAH1 mRNA was expressed in aortic but not macrophage cDNA, and consistent with this expression profile, L-257 selectively inhibited NO production from lipopolysaccharide-treated aorta but not macrophages, in culture. Conscious and anesthetized cardiovascular hemodynamics were monitored using implanted radiotelemetry devices or invasive catheters, respectively. Lipopolysaccharide was administered intravenously to model endotoxemia, and all animals presented with circulatory shock. DDAH1(+/-) mice or L-257-treated rats displayed attenuation in the rate of developed hypotension compared with wild-type littermates or vehicle control animals, respectively.
CONCLUSIONS:
Pharmacological and genetic reduction of DDAH1 activity is protective against the vascular changes observed during endotoxic shock.
AuthorsManasi Nandi, Peter Kelly, Belen Torondel, Zhen Wang, Anna Starr, Yue Ma, Philip Cunningham, Raymond Stidwill, James Leiper
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 11 Pg. 2589-97 (Nov 2012) ISSN: 1524-4636 [Electronic] United States
PMID22995517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • RNA, Messenger
  • Recombinant Proteins
  • Nitric Oxide
  • Amidohydrolases
  • dimethylargininase
Topics
  • Amidohydrolases (antagonists & inhibitors, deficiency, genetics)
  • Animals
  • Cell Line
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelial Cells (drug effects, enzymology)
  • Enzyme Inhibitors (pharmacology)
  • Gene Expression Regulation, Enzymologic
  • Hemodynamics (drug effects)
  • Humans
  • Hypotension (chemically induced, genetics, metabolism, physiopathology, prevention & control)
  • Lipopolysaccharides
  • Macrophages (drug effects, enzymology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Nitric Oxide (metabolism)
  • RNA, Messenger (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins (antagonists & inhibitors, metabolism)
  • Shock, Septic (chemically induced, genetics, metabolism, physiopathology, prevention & control)
  • Time Factors
  • Tissue Culture Techniques

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